Non-syndromic Tooth Agenesis Research Articles

Exonic and Intronic WNT10A Variants Isolated from Korean Children with Non-Syndromic Tooth Agenesis

Background/Objectives: Tooth agenesis (TA) is a developmental anomaly prevalent in humans. It is particularly significant in children and adolescents because it is related to esthetic, physiological, and functional problems, including malocclusion, periodontal damage, and insufficient alveolar growth. WNT10A mutations have been identified as the main genetic alterations associated with tooth agenesis. Most previous studies have investigated WNT10A mutations in patients with tooth agenesis using single nucleotide polymorphism (SNP) arrays or exome sequencing. In this study, we conducted a comprehensive profiling of mutations within the exons and introns of WNT10A in Korean patients with non-syndromic tooth agenesis. Methods: Saliva samples were collected from Korean children and adolescents with non-syndromic tooth agenesis. Tagmentation-based sequencing was conducted to acquire mutation information for all exonic and intronic bases of the WNT10A gene. Results: Mutations were detected exclusively in the patient samples: 629C>G and 1100C>T in exon 1, 1977T>C in intron 1, 10256C>T and 10382G>A in exon 3, and 15953G>A in intron 4. Additional mutations were also observed at high ratios in the patient samples. Conclusions: The mutations identified in this study differ from previous findings. These results may provide useful information for understanding the pathogenicity of WNT10A mutations in Korean patients with tooth agenesis and support future diagnostic and therapeutic approaches.

Novel MSX1 Gene Variants in Chinese Children with Non-Syndromic Tooth Agenesis: A Clinical and Genetic Analysis.

Tooth agenesis is the most frequently occurring genetic developmental anomaly in clinical dentistry. The MSX1 gene, essential for tooth development, has been associated with non-syndromic tooth agenesis. This study aims to identify novel MSX1 variants associated with this condition and to understand their impact on tooth development. This study involved the genetic analysis of two children presenting with non-syndromic tooth agenesis. Conservation analysis and 3D structural modeling were conducted to assess the pathogenicity of these variants. Additionally, a review of 108 patients with known MSX1 variants was performed to identify patterns of tooth agenesis. We discovered two novel MSX1 variants, c.823 T>G and c.890 A>G, located in the second exon of the MSX1 gene. The identified MSX1 variants, c.823 T>G and c.890 A>G, were predicted to be pathogenic. Conservation analysis showed that the impacted amino acids are highly conserved across species, and 3D structural analysis indicated potential disruptions to protein function. Among the 108 patients reviewed, a consistent pattern of tooth agenesis was observed, with the most frequently missing teeth being the maxillary second premolars, the mandibular second premolars, and the maxillary first premolars. This research broadens the known range of MSX1 gene variants and deepens our comprehension of the genetic foundations of non-syndromic tooth agenesis. The findings provide valuable insights for genetic counseling and future research into tooth development, emphasizing the importance of MSX1 in dental anomalies.

A novel PAX9 variant in a Chinese family with non-syndromic oligodontia and genotype-phenotype analysis of PAX9variants.

This study aimed to identifyPAX9variants in non-syndromic tooth agenesis families of China, as well as to analyze the genotype⁃phenotype of non-syndromic tooth agenesis caused by PAX9variants, which can provide a basis for the genetic diagnosis of tooth agenesis. We collected the data of 44 patients with non-syndromic oligodontia who underwent treatment at Stomatological Hospital of Hebei Medical University between 2018 and 2023. Whole-exome sequencing was performed on the peripheral blood of the proband and its core family members, and the variants were verified by Sanger sequencing. Pathogenicity analysis and function prediction of the variants were performed using bioinformatics tools. The correlation between the genotype of PAX9 variant and its corresponding phenotype was examined by reviewing 55 publications retrieved from PubMed. The studies involved 232 tooth agenesis patients with PAX9 variants. A novel PAX9 c.447delG (p.Pro150Argfs*62) and a reported PAX9 c.406C>T (p.Gln136*) were identified in two Chinese families. Through bioinformatics analysis and three-dimensional structural modeling, we postulated that the frameshift variant was pathogenic. The outcome was the premature cessation of PAX9 protein, which caused severe structural and functional deficiencies. Summarizing the PAX9 genotype-phenotype relationship revealed that patients carrying the PAX9 variant commonly led to loss of the second molars. We identified the novel PAX9 c.447delG (p.Pro150Argfs*62) in a Chinese family of non-syndromic oligodontia, expanding the known variant spectrum of PAX9. The most susceptible tooth position for PAX9 variants of tooth agenesis was the second molars and the deciduous molars during the deciduous dentition.

Treatment strategy for patient with non-syndromic tooth agenesis: a case report and literature review

BackgroundNon-syndromic tooth agenesis (NSTA) is a type of ectodermal dysplasia (ED) in which patients with non-syndromic oligodontia may only affect teeth. No pathological findings were found in other tissues of the ectodermal. Herein, we report a case of a NSTA patient with severe dental anxiety and poor oral health.Case presentationA 5-year-old boy without systemic diseases presented as a patient with oligodontia, extensive caries, and periapical periodontitis. Molecular genetic analysis found a mutation in the Ectodysplasin A (EDA) gene, confirming the diagnosis of NSTA.ConclusionTooth agenesis (TA) is the most common ectodermal developmental abnormality in humans. Non-syndromic oligodontia patients often seek treatment in the department of stomatology. Because of their complex oral conditions, these patients should be provided with a systematic and personalized treatment plan.

Next-generation sequencing applied to non-syndromic tooth agenesis: A systematic literature review

BackgroundTo explore the genetic profile of Non-Syndromic Tooth Agenesis (NSTA) detected by Next-Generation Sequencing (NGS). MethodsA systematic review exploring PubMed, ScienceDirect, BMC, LILACS, Scopus, Embase and Web of Science was conducted. Studies investigating the genetic alterations involved in NSTA detected by NGS were selected. Data were extracted and risks of biases were evaluated. ResultsAfter screening 191 articles, 4 articles were included in this study. The overall qualities of the studies were considered high for 3 papers and low for the other one. Among 636 permanent missing teeth, second premolars and lateral incisors were the most affected ones. Whole exome sequencing and gene panel sequencing focusing either on exons plus exon-intron boundaries, or only exons were focused. Mutations on MSX1, PAX9, EDA, EDAR, AXIN2, WNT10A, LAMA3, DKK1, COL17A1, IRF6, LRP6, CHD7, CREBBP, EVC, LEF1, ROR2, TBX22, FGFR1 and TP63 were identified. Allelic frequencies of some variants were reported only in polish and Turkish populations and showing both slight and important variations. Moreover, Functional analysis was performed only for LRP6 variant in Turkish population. The published in-silico analyses of the proteins corresponding to the mutated LAMA3, MSX1 and WNT10 genes revealed a truncated protein for MSX1 and disulfide bridges destabilization for LAMA3 and WNT10A. ConclusionsSeveral genes were associated with NSTA and the candidacy of novel genes was suggested. Further research focusing on the exon-intron boundaries and the impact of mutations on the antisense transcripts should be carried out to better puzzle out their impact on the protein translation and structure.

A novel WNT10A variant impairs the homeostasis of alveolar bone mesenchymal stem cells

AbstractObjectivesTo explore the influence of a novel WNT10A variant on bone mineral density, proliferation, and osteogenic differentiation capacities of alveolar bone mesenchymal stem cells in humans.Subjects and MethodsWhole‐exome sequencing and Sanger sequencing were utilized to detect gene variants in a family with non‐syndromic tooth agenesis (NSTA). The panoramic mandibular index was calculated on the proband with WNT10A variant and normal controls to evaluate bone mineral density. Alveolar bone mesenchymal stem cells from the proband with a novel WNT10A variant and normal controls were isolated and cultured, then proliferation and osteogenic differentiation capacities were evaluated and compared.ResultsWe identified a novel WNT10A pathogenic missense variant (c.353A > G/p. Tyr118Cys) in a family with NSTA. The panoramic mandibular index of the proband implied a reduction in bone mineral density. Moreover, the proliferation and osteogenic differentiation capacities of alveolar bone mesenchymal stem cells from the proband with WNT10A Tyr118Cys variant were significantly decreased.ConclusionsOur findings broaden the spectrum of WNT10A variants in patients with non‐syndromic oligodontia, suggest an association between WNT10A and the proliferation and osteogenic differentiation of alveolar bone mesenchymal stem cells, and demonstrate that WNT10A is involved in maintaining jaw bone homeostasis.

Non-syndromic tooth agenesis in Latvian adolescent dental patients: a retrospective study with relevant literature review

AimTo investigate the prevalence of tooth agenesis and associated dental anomalies in Latvian adolescent dental patients and compare it to other European countries.DesignCross-sectional study of 2692 11-to-14-year-old patients (39.9% males and 60.1% females) attending Riga Stradins University Institute of Stomatology with panoramic radiographs taken between August 2020 and September 2021. Patients with any genetic syndromes were excluded. Data on tooth agenesis (excluding third molars) and other dental anomalies were recorded.ResultsThe prevalence of tooth agenesis in Latvian adolescent dental patients was 9.3% with no statistically significant difference between genders (χ2 test, p = 0.472). The most commonly missing teeth were mandibular second premolars, followed by upper lateral incisors and upper second premolars. There was a statistically significant association with the presence of other dental anomalies in tooth agenesis patients (p < 0.001).ConclusionsThis study found that the prevalence of non-syndromic tooth agenesis in Latvian adolescent dental patients was 9.3% with no statistically significant differences between the genders. Patients with tooth agenesis have a statistically significant possibility of the presence of other dental anomalies (p < 0.001).

Identification and functional study of a novel variant of PAX9 causing tooth agenesis.

To search for pathogenic gene of a family with non-syndromic tooth agenesis, and explore the possible pathogenesis. A Chinese family with non-syndromic tooth agenesis was recruited and screened for the pathogenic variants by whole exome sequencing technology and co-segregation analysis. The subcellular localization of wild-type and mutant protein was detected by immunofluorescence assay. Cycloheximide chase assay was performed to examine the difference in degradation rate between mutant protein and wild-type one. Dual-luciferase reporter assays were conducted to explore the alterations of mutant protein in the regulation of downstream target genes. A novel missense variant of PAX9 (c.296C>A:p.A99D) was found in this family. Bioinformatics software showed β-return and the random coil were shortened in the p.A99D. The variant did not affect the subcellular localization of PAX9, but the degradation rate of p.A99D was accelerated (p < 0.05). p.A99D inhibited the activation of downstream target gene BMP4 (p < 0.05). This novel variant expands the pathogenic gene spectrum. The variant impaired the protein structure, accelerated the degradation of protein, and inhibited the activation of the downstream target gene BMP4, an upstream molecule in the TGF-β/BMP pathway, which may contribute to tooth agenesis in this family.

Tooth agenesis related to a novel KDF1 variant: A case report and literature review.

To investigate the role of Keratinocyte Differentiation Factor 1 (KDF1) in ectodermal dysplasia (ED) and nonsyndromic tooth agenesis (NSTA) and perform a literature review. Genome sequencing was used to identify genetic variants in a Thai, NSTA proband and validated through Sanger sequencing. Pathogenicity was assessed using ACMG guidelines, MetaRNN and AlphaMissense. A comprehensive review of KDF1/NSTA cases informed genotype-phenotype analysis of the proband. The proband revealed multiple missing teeth, caries and extensive periodontal disease. Deep phenotyping showed no signs of ED beyond tooth agenesis. The identified novel KDF1 variant, p.Ile243Leu, was classified as 'likely pathogenic' by ACMG and predicted as 'detrimental' by MetaRNN and AlphaMissense analyses. Atotal of 14 reviewed KDF1 cases revealed ED-associated variants (3 variants in 8patients) clustering in the region of amino acids 251-275, within the DUF4656 domain, while NSTA-causing variants (4 variants in 6 patients) were typically found in amino- or carboxy-termini to this region. KDF1/NSTA cases exhibited an average of 15 missing teeth, with a higher prevalence in the mandible. This study identifies a novel KDF1 variant-related NSTA in Thai people. The genotype-phenotype correlates suggest a distinctive pattern and tooth agenesis of KDF1-related NSTA.

Congenital Tooth Agenesis and Risk of Early-Onset Cancer

There is some evidence that tooth agenesis (congenital absence of 1 or more teeth) is associated with cancer risk, especially carcinomas of the colon and ovaries, but results of previous studies are conflicting, and associations have not yet been evaluated in a population-based setting. To examine the association between tooth agenesis and specific cancer types before 40 years of age. This population-based cohort study used linking data from nationwide registries in Denmark to assess all Danish live-born singletons born from January 1, 1977, to December 31, 2018, and followed up for up to 40 years. Data were analyzed from January through June 2023. Tooth agenesis as documented by the Danish Central Registry of Odontology (Danish municipal pediatric dental care) from January 1, 1988, to December 31, 2018, and from hospital encounters in the Danish National Patient Registry within the entire study period. The primary outcome was first cancer diagnosis before 40 years of age obtained from the Danish Cancer Registry. Associations between tooth agenesis and specific cancers were estimated by Cox proportional hazards regression as hazard ratios (HRs) with 95% CIs. Analyses were split into age groups: younger than 1 year, 1 to younger than 3 years, 3 to younger than 10 years, 10 to younger than 20 years, 20 to younger than 30 years, and 30 to younger than 40 years. Associations with nonsyndromic tooth agenesis were evaluated after exclusion of individuals with known syndromes. Among 2 501 715 included individuals (1 284 292 [51.3%] male), 70 288 (2.8%) had a diagnosis of tooth agenesis (mean [SD] age at diagnosis, 13.2 [4.1] years) and 26 308 (1.1%) had a diagnosis of early-onset cancer within the study period; 778 individuals had co-occurrence of tooth agenesis and cancer. Overall, tooth agenesis was positively associated with several cancer types, including neuroblastoma (age 1 to <3 years; HR, 4.20; 95% CI, 2.24-7.88), nephroblastoma (age 1 to <3 years; HR, 4.59; 95% CI, 2.37-8.91), hepatoblastoma (age 1 to <3 years; HR, 7.10; 95% CI, 2.70-18.68), osteosarcoma (age 10 to <20 years; HR, 2.19; 95% CI, 1.11-4.32), colorectal carcinomas (age 30 to <40 years; HR, 2.81; 95% CI, 1.38-5.71), and carcinomas of bladder (age 20 to <30 years; HR, 3.35; 95% CI, 1.35-8.30). This cohort study found associations between congenital tooth agenesis and several cancer types, from childhood to early adulthood. Further evaluation of these associations is needed to assess possible clinical implications.

STUDY OF MORPHOLOGICAL VARIATIONS OF THE UPPER FIRST PERMANENT MOLAR IN ASSOCIATION WITH NONSYNDROMIC TOOTH AGENESIS

Genetic factors play a significant role in the complex etiology of non-syndromic tooth agenesis. However, little is known about the genetic components that affect frequently occurring dental variations. Our objectives were to examine the correlation between different morphometric characteristics of the upper first permanent molars and genetic variants of the MSX1 gene in subjects with known genetic changes. Morphometric measurements were made for 31 individuals with non-syndromic tooth agenesis and 69 controls, with known genetic background. A total number of 167 upper permanent molar teeth were examined. To determine the morphological changes of the upper first permanent molars, the dental cast of each participant was examined. We observed statistically significant results at the level of the MSX1 rs12532 and MSX1 rs8670 genes when we examined the presence and the size of the cusp of Carabelli. Variations in morphological results were linked to the MSX1 rs8670 mutation and our results demonstrate that patients without hypodontia have more frequent Carabelli cusps than subjects with hypodontia.

Patterns and sexual dimorphism of non-syndromic hypodontia among a French orthodontic population

ObjectivesThis retrospective study aimed to estimate the prevalence of non-syndromic congenitally missing teeth (CMT) and to explore the frequency of CMT patterns in a French orthodontic population. In addition, the study sought to assess sex-based differences in CMT patterns. DesignPanoramic radiographs of 4569 orthodontic patients between 9 and 21 years-old performed over a 16-year period (2006–2022) were examined to identify non-syndromic tooth agenesis, excluding third molars. A chi-square test or a Fisher exact test were used to determine the difference in the prevalence of tooth agenesis between sex and between arches. ResultsTooth agenesis was observed in 7.3% of the sample (7.9% for females and 6.6% for males). Approximately 86% of the included subjects presented 1 or 2 missing teeth. Single tooth agenesis was significantly more frequent in females than males (p = 0.002, χ2). In total, 23 of the 67 different patterns of CMT observed, were present more than once. 75.5% of male patients and 79.5% of female patients presented one or both missing lateral incisors or second premolars, rarely affected at the same time. This study showed no sex difference in the patterns of tooth agenesis. LimitationsThis study has limitations due to its retrospective nature and our findings apply solely to an orthodontic population from a white ethnic background. ConclusionsClinicians should be aware of this particular incisor/premolar phenotype regardless of biological sex. Issues associated with congenitally missing teeth can be managed more effectively with early teenage diagnosis.

Identification of novel candidate genes associated with non-syndromic tooth agenesis in Mongolian families

ObjectivesThis study aimed to identify genetic variants associated with non-syndromic tooth agenesis (TA) in nine families from Mongolia using whole-exome sequencing (WES) and bioinformatics analysis.Material and methodsThe study enrolled 41 participants, including three inherited and six non-inherited families. WES analysis was performed on 14 saliva samples from individuals with non-syndromic TA. The potential candidate genes were identified through variant filtering and segregation analysis. The filtered variants were then analyzed in silico mutation impact analysis.ResultsWES analysis identified 21 variants associated with TA, and 5 of these variants met all filtering criteria. These variants were located in the exome region of MAST4, ITGA6, PITX2, CACNA1S, and CDON genes. The variant in PITX2 was found in eight participants from inherited and non-inherited families, while the MAST4 variant was identified in 6 participants from inherited families.ConclusionsThe study identified various genetic variant candidates associated with TA in different family groups, with PITX2 being the most commonly identified. Our findings suggest that MAST4 may also be a novel candidate gene for TA due to its association with the Wnt signaling pathway. Additionally, we found that five candidate genes related to focal adhesion and calcium channel complex were significant and essential in tooth development.Clinical relevanceIdentifying new pathogenic genes associated with TA can improve our understanding of the molecular mechanisms underlying the disease, leading to better diagnosis, prevention, and treatment. Early detection of TA based on biomarkers can improve dental management and facilitate orthodontic and prosthetic treatment.

FGFR1 variants contributed to families with tooth agenesis

BackgroundTooth agenesis is a common dental anomaly that can substantially affect both the ability to chew and the esthetic appearance of patients. This study aims to identify possible genetic factors that underlie various forms of tooth agenesis and to investigate the possible molecular mechanisms through which human dental pulp stem cells may play a role in this condition.ResultsUsing whole-exome sequencing of a Han Chinese family with non-syndromic tooth agenesis, a rare mutation in FGFR1 (NM_001174063.2: c.103G > A, p.Gly35Arg) was identified as causative and confirmed by Sanger sequencing. Via GeneMatcher, another family with a known variant (NM_001174063.2: c.1859G > A, p.Arg620Gln) was identified and diagnosed with tooth agenesis and a rare genetic disorder with considerable intrafamilial variability. Fgfr1 is enriched in the ectoderm during early embryonic development of mice and showed sustained low expression during normal embryonic development of Xenopus laevis frogs. Functional studies of the highly conserved missense variant c.103G > A showed deleterious effects. FGFR1 (c.103G > A) was overexpressed compared to wildtype and promoted proliferation while inhibiting apoptosis in HEK293 and human dental pulp stem cells. Moreover, the c.103G > A variant was found to suppress the epithelial-mesenchymal transition. The variant could downregulate ID4 expression and deactivate the TGF-beta signaling pathway by promoting the expression of SMAD6 and SMAD7.ConclusionOur research broadens the mutation spectrum associated with tooth agenesis and enhances understanding of the underlying disease mechanisms of this condition.

The phenotype and genotype of PAX9 mutations causing tooth agenesis.

The purpose of this study was to identify associations between PAX9 mutations and clinical features of non-syndromic tooth agenesis patients. Non-syndromic tooth agenesis patients were found to have mutations by whole exome sequencing (WES). Additionally, conservation analysis and three-dimensional structure prediction were also applied to identify mutated proteins. Eight non-syndromic tooth agenesis probands were identified with PAX9 mutations (c.C112T; C.131_134del; c.G151A; c.189delG; c.305delT; c.C365A; c.394delG; c.A679C). All of the probands were missing more than six teeth (oligodontia). The mutations (c.131_134del,p.R44fs; c.189delG,p.T63fs; c.305delT,p.I102fs and c.394delG,p.G123fs) caused premature termination of the PAX9 protein. The c.C112T(p.R38X) mutation created a truncated protein. Bioinformatic prediction demonstrated that the three missense mutations change the PAX9 structure suggesting the corresponding functional impairments. We reported that eight mutations of PAX9 caused non-syndromic tooth agenesis and analyzed the relationship between PAX9 mutations and non-syndromic tooth agenesis. Our study revealed that PAX9 mutations might be the mutations most associated with non-syndromic tooth agenesis in humans, which greatly broadened the mutation spectrum of PAX9-related non-syndromic tooth agenesis.

The EDA/EDAR/NF-κB pathway in non-syndromic tooth agenesis: A genetic perspective.

Non-syndromic tooth agenesis (NSTA) is one of the most common dental developmental malformations affected by genetic factors predominantly. Among all 36 candidate genes reported in NSTA individuals, EDA, EDAR, and EDARADD play essential roles in ectodermal organ development. As members of the EDA/EDAR/NF-κB signaling pathway, mutations in these genes have been implicated in the pathogenesis of NSTA, as well as hypohidrotic ectodermal dysplasia (HED), a rare genetic disorder that affects multiple ectodermal structures, including teeth. This review provides an overview of the current knowledge on the genetic basis of NSTA, with a focus on the pathogenic effects of the EDA/EDAR/NF-κB signaling pathway and the role of EDA, EDAR, and EDARADD mutations in developmental tooth defects. We also discuss the phenotypic overlap and genetic differences between NSTA and HED. Ultimately, this review highlights the importance of genetic analysis in diagnosing and managing NSTA and related ectodermal disorders, and the need for ongoing research to improve our understanding of these conditions.

Dental Phenotype with Minor Ectodermal Symptoms Suggestive of WNT10A Deficiency

Ectodermal dysplasias (EDs) represent a heterogeneous group of genetic disorders characterized by the abnormal development of ectodermal-derived tissues. They include the involvement of the hair, nails, skin, sweat glands, and teeth. Pathogenic variants in EDA1 (Xq12-13.1; OMIM*300451), EDAR (2q11-q13; OMIM*604095), EDARADD (1q42-q43, OMIM*606603), and WNT10A (2q35; OMIM*606268) genes are responsible for most EDs. Bi-allelic pathogenic variants of WNT10A have been associated with autosomal recessive forms of ED, as well as non-syndromic tooth agenesis (NSTA). The potential phenotypic impact of associated modifier mutations in other ectodysplasin pathway genes has also been pointed out. We present on an 11-year-old Chinese boy with oligodontia, with conical-shaped teeth as the main phenotype, and other very mild ED signs. The genetic study identified the pathogenic variants WNT10A (NM_025216.3): c.310C > T; p. (Arg104Cys) and c.742C > T; p. (Arg248Ter) in compound heterozygosis, confirmed by parental segregation. In addition, the patient had the polymorphism EDAR (NM_022336.4): c.1109T > C, p. (Val370Ala) in homozygosis, named EDAR370. A prominent dental phenotype with minor ectodermal symptoms is very suggestive of WNT10A mutations. In this case, the EDAR370A allele might also attenuate the severity of other ED signs.

Patterns of nonsyndromic tooth agenesis and sexual dimorphism

BackgroundSex dimorphism has been implicated in oral health differences and the pathogenesis of oral diseases, such as tooth agenesis, periodontal disease, dental caries, and tooth loss. Tooth agenesis (TA) is one of the most common developmental anomalies in humans, and its prevalence and patterns are different across ethnic groups. The aim of this study was to investigate the phenotypes and sex-associated patterns of nonsyndromic tooth agenesis (TA) in Thai dental patients.MethodsOne thousand ninety panoramic radiographs were examined. One hundred and one subjects (37 males, 64 females, 15–20 years-old) with nonsyndromic TA were evaluated. Differences in TA prevalence between groups were analyzed using the chi-square or Fisher exact test.ResultsThe TA prevalence, excluding third molars, was 9.3% and more frequently found in the mandible compared with the maxilla. The maxilla demonstrated a higher prevalence of first premolar agenesis than the mandible (P = 0.012), while the mandible had a higher prevalence of second premolar agenesis than the maxilla (P = 0.031). There were significantly more males missing one tooth than females, however, there were more females missing two or more teeth than males (P = 0.042). A missing maxillary left lateral incisor was significantly more frequent in males (P = 0.019), while a missing mandibular right lateral incisor was more frequent in females (P = 0.025). In females, the pattern of two mandibular lateral incisors agenesis was the most common and significantly present in females more than males (P = 0.015). In contrast, the pattern of one mandibular left lateral incisor agenesis was only observed in males and significantly found in males more than females (P = 0.047).ConclusionsWe demonstrate sex-associated differences in nonsyndromic tooth agenesis. The prevalence of single tooth agenesis was higher in males, while that of two or more teeth agenesis was higher in females. We found different patterns of lateral incisor agenesis between males and females.

An inclusive study of deleterious missense PAX9 variants using user-friendly tools reveals structural, functional alterations, as well as potential therapeutic targets.

Mutations in the PAX9 are responsible for non-syndromic tooth agenesis in humans, although their structural and functional consequences on protein phenotype, stability, and posttranslational modifications (PTMs) have not yet been adequately investigated. This in silico study focuses on retrieving the six most deleterious mutations (L21P, R26W, R28P, G51S, I87F, and K91E) of PAX9 that has been linked to severe oligodontia. Several computational algorithm methods were used to determine the deleterious effects of PAX9 mutations. Analysis of gene ontology, protein interactions, and PTMs indicated significant functional changes caused by PAX9 mutations. The structural superimposition of the wild-type and mutant PAX9 variants revealed structural changes in locations that were present in the structures of all six variations. The conserved domain analysis revealed that the areas shared by all six variations contained unique sections that lacked DNA binding or protein-protein interaction sites, suggesting prospective drug target sites for functional restoration. The protein-protein interaction network showed KDM5B as PAX9's strongest interacting partner similar to MSX1. The PAX9 protein's structural conformations, compactness, stiffness, and function may all be impacted by changes, according to MD simulations. In addition, research on cell lines and animal models may be valuable in establishing their specific roles in functional annotations.

Novel PAX9 compound heterozygous variants in a Chinese family with non-syndromic oligodontia and genotype-phenotype analysis of PAX9 variants.

Studies have reported that >91.9% of non-syndromic tooth agenesis cases are caused by seven pathogenic genes. To report novel heterozygous PAX9 variants in a Chinese family with non-syndromic oligodontia and summarize the reported genotype-phenotype relationship of PAX9 variants. We recruited 28 patients with non-syndromic oligodontia who were admitted to the Hospital of Stomatology Hebei Medical University (China) from 2018 to 2021. Peripheral blood was collected from the probands and their core family members for whole-exome sequencing (WES) and variants were verified by Sanger sequencing. Bioinformatics tools were used to predict the pathogenicity of the variants. SWISS-MODEL homology modeling was used to analyze the three-dimensional structural changes of variant proteins. We also analyzed the genotype-phenotype relationships of PAX9 variants. We identified novel compound heterozygous PAX9 variants (reference sequence NM_001372076.1) in a Chinese family with non-syndromic oligodontia: a new missense variant c.1010C>A (p.T337K) in exon 4 and a new frameshift variant c.330_331insGT (p.D113Afs*9) in exon 2, which was identified as the pathogenic variant in this family. This discovery expands the known variant spectrum of PAX9; then, we summarized the phenotypes of non-syndromic oligodontia with PAX9 variants. We found that PAX9 variants commonly lead to loss of the second molars.